Project Summary/Abstract: Congenital structural kidney abnormalities are a major cause of end stage kidney disease (ESRD) and lead to increased risk of morbidity and mortality. Normal nephron (functional unit of the kidney) development is crucial for proper function and homeostasis maintenance in the kidney. Congenital kidney abnormalities often stem from aberrant nephron development resulting in a loss of nephrons. Loss of nephrons has been linked to significant disease such as ESRD susceptibility. One insult that causes decreased nephron number is pathological hypoxia. The VHL/HIF pathway is the major oxygen-sensing pathway expressed in the developing kidney. During normal kidney development, vasculature maturation facilitates increases in oxygen concentration. Molecularly, this process allows for the recruitment of the ubiquitin ligase von Hippel Lindau (VHL) in the nephron progenitors to mark hypoxia-inducible factor 1? (HIF-1?) for proteasomal degradation. We believe this tightly regulated pathway is, in part, responsible for normal nephron development. Furthermore, it has recently been shown that the metabolic profile of nephron progenitors dictates fate decisions such that glycolysis favors self-renewal while mitochondrial respiration leads to differentiation. Based on these recent findings, I believe that VHL is a critical mediator of metabolic switching and nephron progenitor fate decisions. To interrogate my hypothesis, my lab generated a mouse model with a conditional deletion of VHL specifically in the nephron progenitors (VHLNP-/-). I have preliminary data indicating histological defects and renal malformations that appear as early as embryonic day 15.5 (E15.5). Loss of viability of our mouse model occurs around postnatal day 28 (P28) after a reduction in renal function. RNA-sequencing was done using isolated nephron progenitors from E17.5 VHLNP-/- and revealed dysregulation of key genes involved in metabolism (significantly up-regulated glycolysis genes). Additionally, I discovered VHLNP-/- nephron progenitors remain glycolytic even after birth when oxygen is readily available. To continue this investigation, I propose two aims 1) to determine whether VHL mediates a switch between glycolysis and mitochondrial respiration to signal nephron progenitor differentiation and 2) to define the interactions between VHL and mitochondria in nephron progenitor fate decisions. These findings will demonstrate the necessity of strict developmental VHL regulation and serve to identify novel therapeutic targets for kidney disease treatment. !